Hereditary Lymphedema

NORD gratefully acknowledges Joseph L. Feldman, MD, Senior Clinician Educator, Pritzker School of Medicine University of Chicago; Director, Lymphedema Treatment Center, NorthShore University Health System, for assistance in the preparation of this report.

Synonyms of Hereditary Lymphedema

primary lymphedema

Subdivisions of Hereditary Lymphedema

congenital hereditary lymphedema

hereditary lymphedema, type I

lymphedema-distichiasis

lymphedema praecox

lymphedema tarda

Milroy disease

Nonne-Milroy disease

General Discussion

Hereditary lymphedema is a genetic developmental disorder affecting the lymphatic system. It is characterized by swelling (edema) of certain parts of the body. The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. In hereditary lymphedema, lymphatic fluid collects in the subcutaneous tissues under the epidermis due to obstruction, malformation, or underdevelopment (hypoplasia) of various lymphatic vessels. There are three forms of hereditary lymphedema: congenital hereditary lymphedema or Milroy disease; lymphedema praecox or Meige disease; and lymphedema tarda. Symptoms include swelling (lymphedema) and thickening and hardening of the skin in affected areas. In most cases, hereditary lymphedema is inherited as an autosomal dominant trait.
Lymphedema may be classified as primary or secondary. Hereditary lymphedema is also known as primary lymphedema. Secondary lymphedema occurs because of damage to the lymphatic system from surgery, radiation therapy, trauma or infection (e.g. filariasis).
Lipedema is a symmetrical accumulation of subcutaneous fat, most often in the legs. Lipedema occurs almost exclusively in females. Tenderness and bruising are also common. Typically, the feet are not swollen and thickening of the skin of the toes (Stemmer’s sign). Lipedema is frequently misdiagnosed as lymphedema.

Signs & Symptoms

The main symptom associated with hereditary lymphedema is swelling (edema) or puffiness in different parts of the body because of the accumulation of protein-rich fluid (lymph) in the soft layers of tissue under the epidermis (lymphedema). Swelling frequently occurs in one or both legs, but may also be present in the trunk, face, genitalia and arms. When lymphedema develops in the legs, swelling is usually most noticeable in the foot and ankle but may also be present in the calf and thigh.. In some cases, swelling may cause tightness, discomfort and unusual tingling sensations (paresthesias) in the affected areas. The affected area heals poorly even after minor trauma (e.g., cut or insect bite). The skin of the affected area may become abnormally dry, thickened or scaly skin (hyperkeratosis) resulting in a “woody” texture.

Hereditary lymphedema type IA (Milroy’s disease) is characterized by swelling (edema) that is present at or shortly after birth (congenital). In rare cases, edema may develop later in life. The legs are most often affected. The extent and location of edema varies greatly from case to case even among individuals in the same family. In some cases the genitals may also be affected. Additional complications sometimes associated with hereditary lymphedema type I include upslanting toenails, small warty growths on the affected areas (papillomatosis), abnormally large or prominent leg veins, and, in males, urethral abnormalities and the development of a fluid-filled sac along the spermatic cord of the scrotum (hydrocele).

Hereditary lymphedema type II (Meige disease, lymphedema praecox) develops around puberty or shortly thereafter in most individuals. This is the most common type of primary lymphedema. In addition to lymphedema of the legs, other areas of the body such as the arms, face and larynx may be affected. Some individuals may develop yellow nails.

Lymphedema tarda is defined as primary lymphedema occurring after the age of 35. The legs are most often affected, but the arms and other areas may be affected as well.

Hereditary lymphedema may progress and, in some cases, may improve over time. Obesity makes management of lymphedema more difficult. Affected individuals with lymphedema are at risk for developing infections including bacterial infection of the skin and underlying tissue (cellulitis) or infection of the lymphatic vessels (lymphangitis). These infections are characterized by areas of warm, painful and reddened skin. Red skin “streaks” may also develop in the infected area. Increased edema is common. A general feeling of ill health (malaise), fever, chills, and/or headaches may also occur. If left untreated, cellulitis can lead to septicemia, skin abscesses, areas of ulceration, and/or tissue damage (necrosis). Cellulitis is more common in males than females. Athlete’s foot (Tinea pedis) can cause cracks in the interdigital skin, bacterial invasion and cellulitis.

In rare cases of persistent lymphedema, additional complications may develop including fluid (e.g., chyle) accumulation body cavities such as the thorax (chylothorax) and abdomen (chylous ascities). Chyle is a fat-laden cloudy fluid that is absorbed during digestion by the lymphatic vessels located around the intestine. Chyle normally flows through lymphatic vessels into the upper chest (thoracic duct) and is then deposited into veins, where it mixes with blood. In some people with hereditary lymphedema, the lymphatic vessels may rupture or become blocked (obstructed), causing chyle to accumulate in the chest cavity (chylothorax). A patient with primary chylous ascites needs to be on a no-fat diet supplemented with medium chair triglycerides and vitamins. Addition of a diuretic such as Spironolactone has been reported to be a valuable adjunct to dietary control.

Affected individuals may also be at a greater risk than the general population for developing a malignancy at the affected site. These malignancies include angiosarcoma. Angiosarcomas are cancerous tumors that develop from blood or lymphatic vessels. They may occur in any area of the body. A specific type of angiosarcoma is known as lymphagiosarcoma, or Stewart-Treves syndrome. This cancerous tumor may rarely develop in longstanding cases of primary or secondary lymphedema. Angiosarcoma occurs in the lymphedematous extremity but can spread to the adjacent trunk and lungs.

Causes

Many researchers believe that hereditary lymphedema may result from changes (mutations) in one of the different disease genes (genetic heterogeneity). Most cases of hereditary lymphedema type IA and type II are inherited as autosomal dominant traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

Investigators have determined that some cases of hereditary lymphedema type IA (Milroy’s disease) occur because of mutation in the FLT4 gene which encodes of the vascular endothelial growth factor receptor 3 (VEGFR-3) gene located on the long arm (q) on chromosome 5 (5q35.3). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 5q35.3” refers to band 35.3 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Investigators have determined that some cases of hereditary lymphedema type II (Meige disease) occur because of mutations of the ‘forkhead’ family transcription factor (FOXC2) gene located on the long arm (q) of chromosome 16 (16q24.3).

Affected Populations

Hereditary lymphedema affects females more often than males. The estimated prevalence of these disorders is 1 in 6,000 individuals within the general population. Hereditary lymphedema type II (Meige syndrome) is the most common form accounting for approximately 80 percent of cases. The prevalence of hereditary lymphedema type I (Milroy disease) is unknown. Approximately 200 cases have been reported in the medical literature.

Related Disorders

Symptoms of the following disorders can be similar to those of hereditary lymphedema. Comparisons may be useful for a differential diagnosis.

Secondary lymphedema is an acquired disorder that results from obstruction or damage to the lymphatic system. Affected individuals experience swelling due to the accumulation of lymph in the affected area. Secondary lymphedema may occur because of trauma, tumors, or after radiation therapy for cancer or surgery to remove lymph nodes. The most common cause of secondary lymphedema in tropical and subtropical regions is filarial infection in which lymphatic obstruction is caused by a parasitic disease known as lymphatic filariasis. Lymphatic filariasis is caused by three different species of worms known as Brugia malayi, Brugia timori and Wuchereria bancrofti. These worms cause damage and inflammation to the lymphatic system. The worms are introduced into the human body through the bite of infected mosquitoes. Secondary lymphedema is treated by addressing the underlying condition. For example, in lymphatic filariasis, certain drugs are used to kill filarial larvae and worms.

Hereditary lymphedema may be associated with several genetic multisystem disorders including Noonan syndrome, Klippel-Trénaunay-Weber syndrome, lymphedema-hypoparathyroid syndrome, and Turner syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Researchers have determined that hereditary lymphedema type II (Meige syndrome) and three other disorders occur due to different mutations of the same gene (FOXC2). These disorders include yellow nail syndrome, distichiasis-lymphedema syndrome, and lymphedema-ptosis syndrome. The exact relationship between these disorders is unknown.

Yellow nail syndrome is a rare disorder characterized by yellow, thickened, and curved nails with almost complete stoppage of nail growth. Loss of the strip of hardened skin at the base and sides of a fingernail (cuticles) may also occur. Separation of the nails from the nail bed (onycholysis) may cause the nails to fall out. Yellow nail syndrome is usually associated with the presence of fluid in the lungs (plural effusion) and swelling of the arms and legs (lymphedema). Other respiratory problems may occur such as chronic inflammation of the bronchi and bronchioles (bronchiectasis), chronic bronchitis, and/or ongoing inflammation of the membranes that line the sinus cavities (sinusitis). Lymphedema usually occurs around puberty. Yellow nail syndrome occurs because of mutations to the FOXC2 gene and is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Yellow Nail” as your search term in the Rare Disease Database.)

Distichiasis-lymphedema syndrome is a rare autosomal dominant multisystem disorder characterized by swelling due to fluid accumulation that usually occurs around puberty and the development of extra eyelashes along the posterior border of the lid margins (distichiasis). Distichiasis may range from a few extra lashes to a full set of extra eyelashes. Swelling most often affects the legs. Additional anomalies associated with this disorder include cleft palate, droopy eyelids (ptosis), abnormalities of the curved transparent outer layer of fibrous tissue covering the eyeball (cornea), cysts on the spinal cord, an abnormal sensitivity to light (photophobia), and cardiac (heart) defects. Distichiasis-lymphedema syndrome is caused by mutations of the FOXC2 gene and is inherited as an autosomal dominant trait.

Lymphedema-ptosis syndrome is an extremely rare genetic disorder characterized by swelling because of fluid accumulation and droopy eyelids (ptosis). Swelling most often affects the legs. Lymphedema usually occurs at or shortly after puberty. Lymphedema-ptosis syndrome occurs because of mutations of the FOXC2 gene and is inherited as an autosomal dominant trait.

Diagnosis

The diagnosis of hereditary lymphedema may be confirmed by a thorough clinical evaluation and a variety of specialized imaging tests including lymphoscintigraphy, ultrasound, and magnetic resonance imaging (MRI). During lymphoscintigraphy, a radioactively labeled colloid substance is injected intradermally into either the hands or feet. The time required for the tracer to be transported from the point of injection to the regional lymph nodes is recorded. In congenital lymphedema, the tracer may move sluggishly or not move from the site of injection. During an ultrasound, reflected sound waves create an image of the developing fetus. An ultrasound is used to rule out other conditions. A Doppler ultrasound can evaluate venous conditions such as varicose veins and venous blood clots. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI is used to detect findings characteristic of hereditary lymphedema including swelling (edema), a mass surrounded by a sac containing lymph fluid (lymphocele), and the formation of fibrous tissue (fibrosis).

Standard Therapies

Treatment

No gene therapy for hereditary lymphedema is currently available. There is no FDA approved medication to treat lymphedema. Lymphedema risk reduction practices should be followed to reduce complications such as infection and an increase in swelling. Treatment is aimed at reducing swelling and preventing infection. Complete decongestive therapy (CDT) is a form of treatment in which specialized manual techniques (manual lymph drainage) is combined with multilayered compression bandaging, meticulous skin care, exercise, and the use of well-fitted compression garments.. Decongestive and conditioning exercises are important components of CDT. Patients and their parents/caregivers should be counseled on the importance of adhering to lymphedema management recommendations to prevent progression the lymphedema. Antibiotics can be used to treat infections such as cellulitis or as a preventive (prophylactic) measure in individuals with recurrent infections. Athlete’s foot can be treated with antifungal topical medications.

Various surgical techniques have been used to treat individuals with hereditary lymphedema including the surgical joining of small lymphatic vessels to nearby small veins (microsurgical anastomosis) has had some limited success in people with lymphedema. The goal of this surgery is to reduce swelling by creating new pathways for lymphatic fluid flow and “rechanneling” this flow into the venous system. According to the medical literature, these therapies have had only limited effectiveness. Reducing operations are available to remove excess fibrotic tissue in cases of severe lymphedema. Continued use of compression garments is necessary after reducing surgery. Liposuction has not been found to be effective in primary lymphedema.

Individuals with hereditary lymphedema should avoid long periods of immobility with legs in a dependent position. Affected individuals should also take special care to avoid wounds in any affected area because of a reduced resistance to infection. Certain medications such as calcium channel blocking drugs and non-steroidal anti-inflammatory drugs may worsen swelling in the legs and the benefits and risks need to be discussed with the patient’s physician. Excessive salt intake can cause fluid retention.

Genetic counseling will benefit people with hereditary lymphedema and their families. Rehabilitation therapy may be necessary in cases where extreme lymphedema impairs daily activities.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Botanicals such as the Benzopyrones and Saponins (e.g., horse chestnut seed extract) as well as the trace element Selenium have been advocated by some as adjunctive treatments for lymphedema.

Benzopyrones, a group of substances such as coumarin, hydroxethylrutin and flavinoid derivatives, have been used for the treatment of individuals with hereditary lymphedema. These drugs breakdown proteins found in lymph and may stimulation lymph flow thereby reducing lymph accumulation and subsequent swelling. However, the effectiveness of such medications is unproven and under debate. Hepatotoxicity has been reports in up to 6% of the patients taking coumarin. More research is necessary to determine the long-term effectiveness and safety of benzopyrone therapy in individuals with hereditary lymphedema.

Occasionally, drugs that promote fluid mobilization (i.e., diuretics) have been used for people with lymphedema. These medications increase urinary output and may help to reduce swelling in some affected individuals. However, diuretics have not been proven successful in reducing the swelling in primary lymphedema but may be beneficial in patients with mixed origin edema, e.g., phlebolymphedema. The prolonged use of diuretics for the treatment of hereditary lymphedema should be carefully directed by a physician as these medications may have several long-term side effects.

Years Published

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